HGG Advances最新文献

{"title":"De novo missense variants in the RPEL3 domain of PHACTR4 in individuals with overlapping congenital anomalies.","authors":"Erin Torti, Sureni V Mullegama, Isabelle De Bie, Angelique Mercier, Deanna Alexis Carere, Leandra Folk, Jane Juusola, Kristin G Monaghan, Ingrid M Wentzensen, Olivia L Redlich, Adi Reich, Bobbi McGivern","doi":"10.1016/j.xhgg.2025.100421","DOIUrl":"10.1016/j.xhgg.2025.100421","url":null,"abstract":"<p><p>PHACTR4 is proposed to play a role in embryonic development but has yet to be associated with human disease. Here, we report the detailed clinical features of two individuals for whom molecular diagnostic testing was undertaken at a large diagnostic laboratory and who were found to harbor rare, damaging de novo missense variants in the conserved RPEL3 domain of PHACTR4. We also present aggregate information on additional individuals in whom missense variants in the same PHACTR4 gene region were detected. All presented with overlapping phenotypes. Features present in at least half of these individuals included cleft palate, ophthalmologic abnormalities, hearing impairment, dysmorphic facial features, digital anomalies, renal/urinary anomalies, growth delay, microcephaly, abnormal brain imaging, and neurodevelopmental abnormalities; some individuals had additional unique findings as well. The proposed cellular function of PHACTR4 and information from related genes with variants in an RPEL domain suggest that PHACTR4 is a promising candidate gene for human disease. We hope that this report will promote additional research interest in the PHACTR4 gene and lead to the publication of additional cases, to potentially establish a causative relationship and to further delineate the phenotypic and variant spectrum of a PHACTR4-related disorder.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100421"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting variation in the somatic mutation landscape of non-small cell lung cancer.","authors":"Vaibhavi Pathak, Koichi Tazaki, Minal Çalışkan","doi":"10.1016/j.xhgg.2025.100420","DOIUrl":"10.1016/j.xhgg.2025.100420","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is driven by a diverse array of somatic mutations. The vast majority of literature on NSCLC is based on targeted assays or small sample sizes, limiting the ability to provide a comprehensive view of NSCLC mutation profiles. Here, we analyzed genome-wide screen data (including whole genome sequencing and whole exome sequencing) from 1,874 NSCLC subjects to identify molecular subtypes and putative driver genes and to explore the effect of intrinsic and extrinsic factors on somatic mutation profiles. We showed that genome-wide screen data support existing knowledge, such as the TP53:KRAS mutation co-occurrence pattern as a key distinctive feature, but do not reveal additional broad molecular subtypes. In contrast, we demonstrated that low-frequency molecular subtypes or potential driver genes continue to be identified. Using driver gene identification algorithms, we found 50 potential driver genes including ANG, CDK10, CTDSP2, HOXA5, RBP4, and SPHK2, which show evidence of positive selection in NSCLC. Finally, we provided insights into the intrinsic and extrinsic covariates associated with the NSCLC somatic mutation landscape, while confirming associations with ethnicity (TP53 and EGFR), NSCLC subtype (14 genes including KRAS, NFE2L2, and STK11), and smoking history (KRAS, CSMD3, and TP53), we dismissed gene-level associations with sex when other covariates are controlled for. The results presented here represent a concise up-to-date summary of variation in the somatic mutation landscape and carry importance for NSCLC geneticists, medical practitioners, and drug discovery scientists.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100420"},"PeriodicalIF":3.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143504490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.","authors":"Elizabeth Carbonell, Sarah L Stenton, Vijay S Ganesh, Jialan Ma, Grace E VanNoy, Lynn Pais, John N Gaitanis, Melanie C O'Leary, Heidi L Rehm, Anne O'Donnell-Luria","doi":"10.1016/j.xhgg.2025.100419","DOIUrl":"10.1016/j.xhgg.2025.100419","url":null,"abstract":"<p><p>Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100419"},"PeriodicalIF":3.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.","authors":"Jonathan Marquez, Stephen Viviano, Erika Beckman, Jenny Thies, Joshua Friedland-Little, Christina T Lam, Engin Deniz, Emily Shelkowitz","doi":"10.1016/j.xhgg.2025.100418","DOIUrl":"10.1016/j.xhgg.2025.100418","url":null,"abstract":"<p><p>Most of the chemical energy that organisms rely on to support cellular function is generated through oxidative phosphorylation, a metabolic pathway in which electron donors NADH and FADH are oxidized through a series of successive steps to generate adenosine triphosphate. These redox reactions are orchestrated by a series of five protein complexes that sit within the mitochondrial membrane. Deficiency of cytochrome c oxidase, the fourth of these complexes, is a recognized cause of mitochondrial disease. COXFA4 encodes one of the protein subunits of cytochrome c oxidase, and variants in COXFA4 have recently been reported in individuals with a range of symptoms. These symptoms can include feeding difficulties, poor growth, cardiomyopathy, Leigh or Leigh-like disease, and neurodevelopmental delay, although these symptoms vary widely between individuals. However, a mechanistic understanding of the connection between COXFA4 loss and these varied disease manifestations is lacking. Using animal modeling in Xenopus, we explored the ramifications of coxfa4 loss of function on the early developing heart. We then conducted a hypothesis naive analysis of cellular gene expression in the context of COXFA4 deletion and discovered a downstream deficiency in the ornithine decarboxylase pathway. Small-molecule-based modulation of the ornithine decarboxylase pathway in our model modified the extent of disease, including improvement of cardiac function. Our findings point to a mechanism by which COXFA4 dysfunction leads to tissue-specific disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100418"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A proposed role for CDO1 in CNS development: Three children with rare missense variants and a neurological phenotype.","authors":"Leah Rowe, Sureni V Mullegama, Rachel Lombardo, Caitlin Barnes, Shelley Towner, Matthew T Snyder, Alexis Heidlebaugh, Heather Riordan, Amber Begtrup, Amy Crunk, Hong Cui, Amy E Dameron, Leandra Folk, Maria J Guillen Sacoto, Jane Juusola, Olivia L Redlich, Adi Reich, Bobbi McGivern","doi":"10.1016/j.xhgg.2025.100417","DOIUrl":"10.1016/j.xhgg.2025.100417","url":null,"abstract":"<p><p>Cysteine dioxygenase type 1 (CDO1) encodes a non-heme iron dioxygenase, which is involved in cysteine metabolism. While CDO1 has been proposed to be involved in multiple physiological processes, an association with congenital disease has yet to be well defined. This study presents detailed clinical and molecular information on three individuals with overlapping neurological features. All three individuals were found to have rare, conserved, de novo variants clustered in a conserved region of the CDO1 gene with no alternative genetic etiology identified. Features present in all three individuals included electroencephalogram abnormality or seizure, movement abnormalities, hypertonia, encephalopathy, severe microcephaly (-4 SD below mean), growth failure, feeding difficulty, and abnormal brain morphology. Other common features included global developmental delay, sleep disturbance, contractures, cerebral palsy, hyper-reflexia, hearing loss, and hypoxic respiratory failure. This study provides evidence supporting an association between de novo CDO1 missense variants and human neurological disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100417"},"PeriodicalIF":3.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Families' experiences of receiving adult- and pediatric-onset genetic results.","authors":"Jessica Goehringer, Tracey Leitzel, Muki Kunnmann, Alyson E Floyd, Sean O'Dell, Jessica Mozersky, Alanna Kulchak Rahm, Adam H Buchanan","doi":"10.1016/j.xhgg.2025.100416","DOIUrl":"10.1016/j.xhgg.2025.100416","url":null,"abstract":"<p><p>There is a scarcity of empirical data on the potential psychosocial and behavioral effects of returning genomic results for adult-onset conditions not medically actionable in pediatric patients. Potential harms include distress, discrimination, loss of future autonomy, or family functioning changes. The Pediatric Reporting of Genomic Results Study (PRoGRESS) explores outcomes of disclosing pediatric- and adult-onset genomic findings to families in an observational trial. Participants include adolescents (ages 11-17) with a genetic variant identified and returned through Geisinger's MyCode Genomic Screening and Counseling Program and their parents. This program involves returning pathogenic and likely pathogenic variants in a list of genes consistent with the American College of Medical Genetics and Genomics secondary findings list. Parents and adolescents with pediatric- and adult-onset results were invited to participate in interviews at 1 and 12 months post results disclosure. Here, we report the results of a qualitative analysis that included data from 25 participants with a known family history of a variant. Families generally had positive or neutral experiences with learning and adjusting to the results, and, on balance, felt it was beneficial to have the result. Previously proposed hypothetical concerns regarding disclosing adult-onset results to children were not reported in this cohort. Our findings provide guidance on supporting families in preparing for and adjusting to genomic results related to adult-onset conditions, particularly in care-delivery systems that are not designed to support families as the information becomes clinically relevant and provide evidence that longitudinal support may benefit families with an adult- or pediatric-onset result.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100416"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular disease-associated non-coding variants disrupt GATA4-DNA binding and regulatory functions.","authors":"Edwin G Peña-Martínez, Jean L Messon-Bird, Jessica M Rodríguez-Ríos, Rosalba Velázquez-Roig, Diego A Pomales-Matos, Alejandro Rivera-Madera, Leandro Sanabria-Alberto, Adriana C Barreiro-Rosario, Juan A Figueroa-Rosado, Jeancarlos Rivera-Del Valle, Nicole E Muñoz-Páez, Esther A Peterson-Peguero, José A Rodríguez-Martínez","doi":"10.1016/j.xhgg.2025.100415","DOIUrl":"10.1016/j.xhgg.2025.100415","url":null,"abstract":"<p><p>Genome-wide association studies have identified thousands of cardiovascular disease (CVD)-associated variants, with over 90% of them being mapped within the non-coding genome. Non-coding variants in regulatory regions of the genome, such as promoters, enhancers, silencers, and insulators, can alter the function of tissue-specific transcription factors (TFs) and their gene regulatory function. In this work, we used a computational approach to identify and test CVD-associated single-nucleotide polymorphisms (SNPs) that alter the DNA binding of the human cardiac transcription factor GATA4. Using a gapped k-mer support vector machine (GKM SVM) model, we scored CVD-associated SNPs localized in gene regulatory elements in expression quantitative trait loci (eQTL) detected in cardiac tissue to identify variants altering GATA4-DNA binding. We prioritized four variants that resulted in a total loss of GATA4 binding (rs1506537 and rs56992000) or the creation of new GATA4 binding sites (rs2941506 and rs2301249). The identified variants also resulted in significant changes in transcriptional activity proportional to the altered DNA-binding affinities. In summary, we present a comprehensive analysis comprising in silico, in vitro, and cellular evaluation of CVD-associated SNPs predicted to alter GATA4 function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100415"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifaceted analysis of noncoding and coding de novo variants implicates NOTCH signaling pathway in tetralogy of Fallot in Chinese population.","authors":"Qiongfen Lin, Detao Zhang, Peter J Gruber, Paul Kwong-Hang Tam, Vincent Chi-Hang Lui, Zhongluan Wu, Haifa Hong, Kenneth R Chien, Pak Chung Sham, Clara Sze-Man Tang","doi":"10.1016/j.xhgg.2025.100414","DOIUrl":"10.1016/j.xhgg.2025.100414","url":null,"abstract":"<p><p>Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10^-6) and outflow tract morphogenesis (p = 2.2 × 10^-5). Genes with NC DNVs (e.g., EFNB2, HEY2, and PITX2) interacted with NOTCH1 and FLT4 in a tight STRING protein-protein interaction (PPI) network. During the in vitro cardiac differentiation process, these noncoding candidate genes, which harbored potentially damaging regulatory NC DNVs, exhibited co-expression with NOTCH signaling genes and demonstrated dysregulated gene expression at various differentiation stages following NOTCH1 downregulation. In summary, our findings highlight a significant contribution of NC DNVs to TOF and suggest the presence of population genetic heterogeneity. Integrative analyses implicate dysregulation of NOTCH signaling, with converging influences from both coding and noncoding variants, in TOF within the Chinese population.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100414"},"PeriodicalIF":3.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the genetic landscape of susceptibility to multiple primary cancers.","authors":"Pooja Middha, Linda Kachuri, Jovia L Nierenberg, Rebecca E Graff, Taylor B Cavazos, Thomas J Hoffmann, Jie Zhang, Stacey Alexeeff, Laurel Habel, Douglas A Corley, Stephen Van Den Eeden, Lawrence H Kushi, Elad Ziv, Lori C Sakoda, John S Witte","doi":"10.1016/j.xhgg.2025.100413","DOIUrl":"10.1016/j.xhgg.2025.100413","url":null,"abstract":"<p><p>With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (p < 5 × 10^-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when compared with single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100413"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trans-ancestry genome-wide association study of childhood body mass index identifies novel loci and age-specific effects.","authors":"Carolina G Downie, Poojan Shrestha, Samson Okello, Mohammad Yaser, Harold H Lee, Yujie Wang, Mohanraj Krishnan, Hung-Hsin Chen, Anne E Justice, Geetha Chittoor, Navya Shilpa Josyula, Sheila Gahagan, Estela Blanco, Raquel Burrows, Paulina Correa-Burrows, Cecilia Albala, José L Santos, Bárbara Angel, Betsy Lozoff, Fernando Pires Hartwig, Bernardo Horta, Karisa Roxo Brina, Carmen R Isasi, Qibin Qi, Linda C Gallo, Krista M Perreira, Bharat Thyagarajan, Martha Daviglus, Linda Van Horn, Franklyn Gonzalez, Jonathan P Bradfield, Hakon Hakonarson, Struan F A Grant, Jennifer E Below, Janine Felix, Mariaelisa Graff, Kimon Divaris, Kari E North","doi":"10.1016/j.xhgg.2025.100411","DOIUrl":"10.1016/j.xhgg.2025.100411","url":null,"abstract":"<p><p>Over the past 30 years, obesity prevalence has markedly increased globally, including among children. Although genome-wide association studies (GWASs) have identified over 1,000 genetic loci associated with obesity-related traits in adults, the genetic architecture of childhood obesity is less well characterized. Moreover, most childhood obesity GWASs have been restricted to severely obese children, in relatively small sample sizes, and in primarily European-ancestry populations. To identify genetic loci associated with early-childhood body mass index (BMI), we performed GWAS of BMI Z scores in eight ancestrally diverse cohorts: ZOE 2.0 cohort, the Santiago Longitudinal Study (SLS), the Vanderbilt University BioVU biobank, the Geisinger MyCode Health Initiative biobank, Study of Latino (SOL) Youth, Pelotas (Brazil) Birth Cohort, Cameron County Hispanic Cohort (CCHC), and Viva La Familia cohort. We subsequently performed inverse-variance-weighted fixed-effect meta-analysis of these results with previously published GWAS summary statistics of BMI Z scores of children in the Early Growth Genetics (EGG) Consortium and the Norwegian Mother and Child Cohort (MoBa), constituting a final total of 84,804 individuals. We identified 39 genome-wide significant loci associated with childhood BMI, including three putatively novel loci (EFNA5 and DTWD2, RP11-2N5.1 on chromosome 5, and LSM14A on chromosome 19). We also observed a dynamic nature of genetic loci-BMI associations across the life course, with distinct effects across childhood and adulthood, highlighting possible critical periods for early-childhood interventions. These findings strengthen calls for larger population-based studies of children across age strata and across diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100411"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}